Abstract The disorders collectively known as inflammatory bowel disease (IBD) including Crohn?s disease (CD) and ulcerative colitis (UC) affect up to one and a half million Americans. Both result from uncontrolled chronic inflammatory activity in the GI tract. Most therapeutic agents act by down-regulating inflammation, are not curative and suffer from significant side-effects. Forty to 60% of patients do not obtain benefit long-term from available treatments and have a two-fold greater risk of developing colorectal cancer. Thus, there is an unmet need for new therapeutic modalities. Numerous groups, including our own, have reported promising results with the anti-inflammatory cytokine interlukin-10 (IL-10). However, clinical trials with systemic IL-10 in IBD patients have been disappointing. Rapid clearance, dose limiting toxicities and lack of oral bioavailability have precluded use. We have developed a proprietary sustained-release formulation of IL-10, which upon oral administration is preferentially taken up and retained in the immune structures of the gut and restores immune homeostasis in the inflamed colon. Preliminary studies in IL-10-/- murine model of colitis demonstrated that oral IL-10 ameliorated both early and established disease without overt toxicity or systemic exposure. In light of these findings, this application will test the therapeutic efficacy of oral IL-10 in two commonly utilized acute and chronic models of murine colitis. In Aim 1 treatment will be evaluated in the acute dextran sulphate sodium (DSS) model; dose and schedule will be optimized; and finally the effect of IL-10 on the phenotype and functional properties of colonic lamina propria and mesenteric lymph node mononuclear cells will be examined. Aim 2 will test efficacy in the CD4+CD25- T-cell reconstituted SCID mouse model of chronic colitis, monitor potential side effects and determine how chronic treatment affects inflammatory mononuclear cell activity in the long-term. Local and sustained release of IL-10 directly to the disease microenvironment from orally- administered IL-10 loaded microspheres is expected to provide several advantages, including: a) the ability to directly target the gut leading to increased efficacy, b) the requirement for significantly lower doses, thus reducing the toxic side-effects associated with systemic administration and c) sustained-release, reducing the need for frequent administration.